Bis-(substituted benzyl) malonic acid esters

ABSTRACT

Bis-substituted benzyl acetic acids, e.g., bis-(ppivaloylbenzyl)acetic acid, are prepared by hydrolyzing and decarboxylating a corresponding bis-(p-pivaloylbenzyl)malonic acid diethyl ester and are useful as hypolipidemic agents.

United States Patent Houlihan et al.

[451 May 20, 1975 BIS-(SUBSTITUTED BENZYL) MALONIC ACID ESTERSInventors: William J. l-loulihan, Mountain Lakes; Jeffrey Nadelson, LakeParsippany, both of NJ.

Assignee: Sandoz-Wander, lnc., E. Hanover,

Filed: Dec. 4, 1973 Appl. No.: 421,673

Related U.S. Application Data Continuation-impart of Ser. No. 403,225,Oct. 3, i973, abandoned, which is a continuation-in-part of Ser. No.333,892, Feb 20, 1973, abandoned.

U.S. Cl.... 260/475 SC; 260/473 R; 260/515 A;

Int. Cl. C07c 69/76 Field of Search 260/473 R, 475 SC References CitedOTHER PUBLICATIONS Wittig et al., C.A., 23:4942-3, (1929). Emerson etal., C.A., 45:4224a, (1950). Skinner et al., C.A., 54:2239f, (1959).

Primary Examiner-Lorraine A. Weinberger Assistant Examiner-MichaelShippen Attorney, Agent, or FirmGerald D. Sharkin; Robert S. Honor [57]ABSTRACT 4 Claims, No Drawings BIS-(SUBSTITUTED BENZYL) MALONIC ACIDESTERS This application is a continuation-in-part of copendingapplication Ser. No. 403,225, filed Oct. 3, 1973 and now abandoned whichin turn is a continuation-in-part of copending application Ser. No.333,892, filed Feb. 20, 1973 and now abandoned.

This invention relates to bis-substituted benzyl acetic acids whichexhibit hypolipidemic activity. In particular, it relates to substitutedbenzyl acetic acids; pharmaceutically acceptable salts, theirpreparation and intermediates thereof.

The compounds of this invention may be represented by the formula:

where R, each independently represents hydrogen, fluoro or chloro, andstraight chain lower alkoxy, i.e., straight chain alkoxy having 1 to 4carbon atoms, e.g. and methoxy, ethoxy, isopropoxy or the like and R andR each independently represent alkyl having 1 to 2 carbon atoms, i.e.methyl or ethyl.

The compounds of formula (I) are prepared according to the followingreaction scheme:

R a l l H R C C 3 l base c113 mnefi1- acid a co R C C 3 u c n 0 R 1 1| 3c 3 CU n 2 i R C C 3 l h CH3 0 I (I) where R each independentlyrepresents lower alkyl having 1 to 4 carbon atoms, e.g. methyl, ethyl,isopropyl and the like, and R R and R are as defined above. Thecompounds of formula (I) are prepared by hydrolyzing and decarboxylatinga compound of the formula (II). The compounds of formula (II) arehydrolyzed employing conventional techniques with an alkali metal basesuch as sodium or potassium hydroxide, the latter being especiallypreferred, followed by acidification and spontaneous decarboxylationusing a mineral acid in the presence of an aqueous solvent. Suitableacids which can be employed include hydrochloric acid, sulfuric acid andhydrobromic acid, preferably hydrochloric acid. The aqueous solvent canbe water or a mixture of water and a water soluble organic solvent e.g.,lower alkanols having 1 to 4 carbon atoms e.g. methanol, ethanol and thelike. The temperature of the reaction is not critical, but it ispreferred that the reaction be carried out at the reflux temperature ofthe solvent. The reaction is run from about 12 to 36 hours, perferablyabout 15 to 20 hours. The product is recovered by conventionaltechniques e.g. crystallization.

The compounds of formula (II) are prepared according to the followingreaction scheme:

ClLdr 1 2 fiO R R l 05 1 l co a c o I (IV) R -f-CH 3 (III) C113 72 co a.R C C 2 u where D is an alkali metal such "as sodium or potassium and- RR R and R are as defined above.

The compounds of formula (II) are prepared by treating a compound of theformula (III) with a compound of the formula (IV) in the presence of astrong base such as sodium hydride, potassium hydride, sodium ethoxideor potassium ethoxide, the latter being especially preferred forincrease yields. The reaction is carried out in the presence of an inertorganic solvent such as lower alkanols, methanol, ethanol and the like,dimethylformamide or dimethylacetamied, the latter being especiallypreferred. The temperature of the reaction is not critical, but it ispreferred that the reaction be run from about 20 to 30C, preferablyabout 25C. The reaction is run from about 12 to 24 hours, preferablyabout 16 to 20 hours. The product is recovered using conventionaltechniques eg, crystallization.

The compounds of formula (III) are prepared according to the followingreaction scheme: 3

where R,, R and R are as defined above.

The compounds of formula (III) are prepared by treating a compound offormula (V) with a brominating agent in the presence of an inert organicsolvent and free radical initiator. The brominating agent which can beused is bromine, N-bromosuccinimide, N- bromo phthalamide,N-bromo-acetamide and the like. The particular agent used is notcritical, but N- bromosuccinamide is preferred. In the preferredprocess, the free radical initiator used is an organic peroxide,especially benzoyl peroxide. The reaction can also be carried out underultraviolet light. Although the particular solvent used is not critical,the preferred solvents are the halogenated hydrocarbons such asmethylene dichloride, chloroform. carbon tetrachloride and the like,although the aromatic hydrocarbons such as benzene can also be employed.The temperature of the reaction is not ciritcal, but reflux temperatureof the solvent is preferred. The reaction is run for about 12 to 48hours; preferably about 18 to 25 hours. The product is recovered byconventional techniques,,e.g., crystallization.

Many of the compounds of formula (IV) and (V) are known and may beprepared by methods described in the literature. The compounds offormula (IV) and (V) not specifically disclosed may be prepared byanalogous methods from known starting materials.

It will be understood that certain of the compounds of formulae (1) and(II) in which the benzyl groups are not identical may exist in the formof optically active isomers. The separation and recovery of therespective isomers may be readily accomplished employing conventionaltechniques and such isomers are included within the scope of theinvention.

The compounds of formulae (I) and (II) are useful because they possesspharmacological activity in animals as hypolipidemic agents,particularly as hyperlipoproteinemic agents as indicated by the fall incholesterol and triglyceride levels in male albino Wistar rats weighing110-130 g initially. The rats are maintained on drug-free laboratorychow diet for 7 days and then divided into groups of 8 to 10 animals.Each group with the exception of the control is then given orally 30milligrams per kilogram of body weight per diem of the compound for 6days. At the end of this period, the animals are anesthetized withsodium hexobarbital and bled from the carotid arteries. Serum or plasmasamples are collected, and 1.0 ml samples of the serum are added to 9.0ml redistilled isopropanol. Two autoanalyz er cupsful of a mixture ofzeolite-copper hydroxide and Lloydds reagent (Kessler, G., and Lederer,I-I., 1965, Technicon Symposium, Mediad Inc., New York, (345-347) areadded, and the mixture is shaken for 1 hour. Cholesterol andtriglyceride levels are determined simultaneously on the same sample byTechnicon N 24 A (cholesterol) and N-78 (triglyceride) methodology. Themean total serum cholesterol levels are then computed and thehypocholesterolemic activity is expressed as the fall in cholesterollevels as a percentage of the control level. The change in serumtriglyceride levels induced by the drug is computed as a percentage ofthe control triglyceride levels.

For such usage, the compounds (I) and (II) may be combined with apharmaceutically acceptable carrier or adjuvant and may be administeredorally or parenterally as such or admixed with conventionalpharmacuetical carriers. They may be administered in such forms astablets, dispersible powers, granules, capsules, syrups and elixirs andparenterally as solutions, suspensions, dispersions, emulsions and thelike, e.g. a sterile injectable aqueous solution. The dosage will varydepending upon the mode of administration utilized and the particularcompound employed.

The compounds for formula (I) may be similarly administered in the formof their non-toxic pharmaceutically acceptable salts. Such salts possessthe same order of activity as the free acid, and are readily prepared byreacting the acid with an appropriate hydroxide or oxide and,accordingly, are included within the scope of this invention.Representative of such salts are the alkali metal salts, e.g. sodium,potassium and the like, and the alkaline earth metal salts such asmagnesium, calcium and the like.

The hypolipidemic effective dosage of compounds (I) and (II) employed inthe alleviation of lipidemia may vary depending on the particularcompound employed and the severity of the condition being treated.However, in general, satisfactory results are obtained when thecompounds of formulae (I) and (II) are administered at a daily dosage offrom about 2.0 milligrams to about 250 milligrams per kilogram of animalbody weight, preferably 10.0 milligrams to about 250 milligrams perkilogram given in divided doses two to four times a day, or in sustainedrelease form. For most large mammals, the total daily dosage is fromabout milligrams to about 3000 milligrams, preferably 700 milligrams to3000 milligrams. Dosage forms suitable for internal use comprise fromabout 37.5 to about 1500 milligrams of the active compound in intimateadmixture with a solid or liquid pharmaceutically acceptable carrier ordiluent.

A representative formulation suitable for oral administration 2 to 4times a day for the treatment of lipidemia is a capsule prepared bystandard encapsulating techniques which contains the following:

Ingredients Weight (mg) bis-(p-pivaloylbenzyl)acetic acid 150 inertsolid diluent (starch, lactose, 300 kaolin.)

EXAMPLE I a-bromo-p-pivaloyl toluene.

mixture is refluxed for an additional 1% hours. The resulting Grignardsolution is added dropwise to acold solution of 128.0 g pivaloylchloride (1.06 mole) in 500 ml dry tetrahydrofuran at a rate thatmaintains the temperature at to C. The solution is stirred for anadditional 1 /2 hours at 0 and then at room temperature for 18 hours.The mixture is then cooled to 0 and hydrolyzed by the addition of 100 ml2N hydrochloric acid. The layers are separated and 200 ml of ether isadded to the organic phases which is then washed respectively with 100ml 2N hydrochloric acid, 100 ml. sodium bicarbonate solution and 100 ml.saturated sodium chloride. The resulting layer is dried over anhydroussodium sulfate, filtered, and the solvent is removed in vacuo to givep-pivaloyl toluene (b.p. 8084C/0.7 mm, m, 1.5108). A mixture of 156.3 g.(0.886 mole) of the resulting p-pivaloyl toluene is then added to 157.8g. (0.886) mole) N-bromosuccinimide, 4.0 g (0.016 mole) benzoyl peroxideand 150 ml. carbon tetrachloride and heated at reflux for 18 hours. Themixture is cooled and filtered and the resulting precipitate is washedwith carbon tetrachloride. The solvents are removed in vacuo and theresulting oil is distilled in vacuo to give a-bromo-p-pivaloyl toluene(b.p. 124-132/0.7 mm, n l.5546-V.P.C. 96% monobromo 4%-dibromo).

Following the above procedure and using in place of 4-bromotolueneequivalent amounts of:

a. 4-bromo-2-chlorotoluene or b. 4-bromo-2-methoxytoluene, there isobtained a. a-bromo-2-chloro-4-pivaloyl toluene or b.a-bromo-2methoxy-4-pivaloyl toluene, respectively.

EXAMPLE 2 bis-(p-pivaloyl benzyl)malonic acid diethyl ester.

To a cold suspension of 4.66 g (0.194) mole of sodium hydride in 200 mldimethylacetamide there is added dropwise 28.2 g (0.176 mole) diethylmalonate in 80 ml of dimethylacetamide maintaining the temperaturebetween 0 and 5C. Stirring is initiated for 2 hours at room-temperatureand there is then added 40.8 g(0.16 mole) of a a-bromo-p-pivaloyltoluene in 200 ml of dimethylacetamide maintaining the reactiontemperature between and 30C. Stirring is continued overnight at roomtemperature. Water is then added and the excess dimethylacetamide isremoved in vacuo, and the resulting residue is partitioned betweenpetroleum ether and water. The layers are .washed with water, and saltwater, dried and evaporated in vacuo. The residue is then distilled invacuo and crystallized from petroleum ether at 50C to givebis-(p-pivaloylbenzyl)malonic acid. diethyl ester, m.p. 65 to 67C.

ether, the ether extracted with 2N sodium hydroxide and the basicsolution is made acidic at 0C with concentrated hydrochloric acid,extracted with ether, and the ether is then dried and evaporated. Theresulting residue is crystallized from ether/petroleum ether to givebis-(p-pivaloylbenzyl) acetic acid, m.p. 107109C.

Following the above procedure and using in place-ofbis-(p-pivaloylbenzyl) malonic acid diethyl ester, an equivalent amountof a. bis-(2-chloro-p-pivaloylbenzyl)malonic acid diethyl ester, or b.bis-(2-methoxy-p-pivaloylbenzyl)malonic acid diethyl ester there isobtained a. bis-(2-chloro-p-pivaloylbenzyl)acetic acid, or

b. bis-( 2-methoxy-p-pivaloylbenzyl)acetic acid, re-

spectively.

The bis-(p-pivaloylbenzyl)acetic acid of this example is an effectivehypolipidemic agent when orally administered to an animal suffering fromlipidemia at a'dosage of 150 mg 4 times per day.

What is claimed is:

1. A compound of the formula R3 g 6 00 R R I i g where R representshydrogen, fluoro or chloro or straight chain lower alkoxy, and

R and R each independently represent lower alkyl 5 having 1 to 2 carbonatoms, and

R each independently represents lower alkyl having 1 to 4 carbon atoms.2. A compound of the formula EXAMPLE 3 bis-(p-pivaloylbenzyDacetic acidTo a solution of 10g (0.03 mole) of bis-(ppivaloylbenzyl) malonic aciddiethyl ester in 45 ml of ethanol and 45 ml of water, .there is added8.4 g (0.15 mole) potassium hydroxide which is reluxed for 5 hours. Thesolvents are removed in vacuo and the residue partitioned between etherand water. The aqueous layer is made acidic at 0 C with concentratedhydrochloric acid, extracted with ether, dried and evaporated. Theresulting oil is treated with 200 ml of concentrated hydrochloric acidand the mixture is refluxed for 20 hours. The cooled mixture isextracted with .where R, is as defined in claim 1. 3. A compound of theformula where R; and R are as defined in claim 1.

4. The compound of claim 1 which is bis-(p-pivaloyl benzyl) malonic aciddiethyl ester.

1. A COMPOUND OF THE FORMULA
 2. A compound of the formula
 3. A compoundof the formula
 4. The compound of claim 1 which is bis-(p-pivaloylbenzyl) malonic acid diethyl ester.